Delivery of a therapeutic agent via an implantable device is desirable for a variety of applications. For example, therapeutic agents applied to an implantable device may treat or mitigate such undesirable conditions as restenosis, inflammation, tumor development, or thrombosis formation.
Procedures for mitigating such conditions may include implantation of a device comprising a therapeutic agent. For example, implantations of stents during angioplasty procedures have substantially advanced the treatment of occluded blood vessels. Occasionally, angioplasty may be followed by an abrupt closure of the vessel or by a more gradual closure of the vessel, commonly known as “restenosis.” Acute closure may result from an elastic rebound of the vessel wall and/or by the deposition of blood platelets and fibrin along a damaged length of the newly opened blood vessel. Restenosis may result from the natural healing reaction to the injury to the vessel wall (known as intimal hyperplasia), which involves the migration and proliferation of medial smooth muscle cells that continues until the vessel is again occluded.
To prevent such vessel occlusion, stents have been implanted within a body vessel. However, restenosis may still occur over the length of the stent and/or past the ends of the stent where the inward forces of the stenosis are unopposed. To reduce this problem, one or more therapeutic agents may be administered to the patient. For example, a therapeutic agent may be locally administered through a catheter positioned within the body vessel near the stent, or by coating the stent with the therapeutic agent.
Desirably, a medical device coated with a therapeutic agent is adapted to expose tissue within the body to the therapeutic agent over a desired time interval, such as by releasing the therapeutic agent. Desirably, the therapeutic agent is released within the body at a reproducible and predictable fashion so as to optimize the benefit of the therapeutic agent to the patient over the desired period of time. Providing coated medical devices adapted to release a therapeutic agent at a desired rate over a period of time is one challenge in designing implantable medical devices. For example, a coated medical device may release a therapeutic agent at a greater rate than desired upon implantation, and subsequently release the therapeutic agent at a slower rate than desired at some time after implantation.
The design configuration of an implantable device can be adapted to control the release of therapeutic agent from the device. For example, a therapeutic agent can be included in the implantable medical device, such as an implantable frame comprising a porous biostable material optionally mixed with or coated on top of a therapeutic agent. Current Drug Eluting Stents (DES) may incorporate permanent biostable polymers into their coatings. For example, U.S. Patent Applications 2005/0176678 and 2005/0060028 describe polymeric bioabsorbable coatings including polylactic acid and polyglycolic acid. However, there is some concern that these permanent polymers may lead to late thrombosis. It has been shown that various bioabsorbable polymers may produce an excess tissue response (Heart. 1998 April; 79(4):319-23). Implanted polymer coatings have been associated with a significant inflammatory and exaggerated neointimal proliferative response, as well as enhanced thrombotic response (Circulation. 1996; 94(7):1494-5).
As a consequence, there has been interest in recent years in developing alternative coating configurations that do not require durable polymers, but include a bioabsorbable material. Naturally occurring bioabsorbable coatings with improved biocompatibility are desirable. One suitable naturally-derived material is corn-derived proteins called zeins that constitute most of the storage proteins of maize seed. During development of the kernel, zein accretions form in the peripheral regions of the lumen of the rough endoplasmin reticulum. These ultimately develop into cytoplasmic deposits called vesicular protein bodies ranging in size from 1 to 3 μm in diameter. At maturity, zein comprises more than half of all extractable proteins found in the maize endosperm. Human liver cells and mouse fibroblast cells have been shown to attach to and proliferate on zein, suggesting that zein may be biocompatible. J. Dong et al., “Basic study of corn protein, zein, as a biomaterial in tissue engineering, surface morphology and biocompatibility,” Biomaterials 25, 4691-4697 (2004). Further, Wang et al. describe a cardiovascular device coating comprising zein microspheres and heparin. H-J. Wang et al., “Heparin-loaded zein microsphere film and hemocompatibility,” Journal of Controlled Release 105, 120-131 (2005).
However, zein coatings may be dry and brittle. There is some concern this characteristic may lead to tearing and cracks appearing in a zein coating, especially when the zein coating is thin. Further, an implantable device may be subjected to mechanical straining (e.g., crimping, loading into a delivery device, sterilizing) that may introduce cracks and peeling in a zein coating on the device.